The B24-B25 peptide bond of insulin was replaced by an ester bond. To
our knowledge this is the first replacement of a main chain atom repor
ted for the hormone. It is meant to eliminate a structurally important
H-bond between the imino group of B25 and the carbonyl oxygen of A19,
and consequently to enhance detachment of the C-terminal B chain from
the underlying A chain. On the basis of independent experimental evid
ence this very conformational change is believed to be a prerequisite
for receptor binding. It was thus anticipated that increased flexibili
ty would increase receptor binding and activity. Intriguingly, porcine
[B24-B25 CO-O]insulin (depsi-insulin) and likewise [B24-B25 CO-O]des-
(B26-B30)insulin-B25-amide (depsi-DPI-amide) were found to be only 3-4
% potent.